tbuckley/cabot-search huggingface dataset:
Two-year effects of semaglutide in adults with overweight or obesity: the STEP 5 trial
Authors: W Timothy Garvey, Rachel L Batterham, Meena Bhatta, Silvio Buscemi, Louise N Christensen, Juan P Frias, Esteban Jódar, Kristian Kandler, Georgia Rigas, Thomas A Wadden, Sean Wharton
Journal: Nature Medicine (2022)

Abstract The STEP 5 trial assessed the efficacy and safety of once-weekly subcutaneous semaglutide 2.4 mg versus placebo (both plus behavioral intervention) for long-term treatment of adults with obesity, or overweight with at least one weight-related comorbidity, without diabetes. The co-primary endpoints were the percentage change in body weight and achievement of weight loss of ≥5% at week 104. Efficacy was assessed among all randomized participants regardless of treatment discontinuation or rescue intervention. From 5 October 2018 to 1 February 2019, 304 participants were randomly assigned to semaglutide 2.4 mg ( n = 152) or placebo ( n = 152), 92.8% of whom completed the trial (attended the end-of-trial safety visit). Most participants were female (236 (77.6%)) and white (283 (93.1%)), with a mean (s.d.) age of 47.3 (11.0) years, body mass index of 38.5 (6.9) kg m –2 and weight of 106.0 (22.0) kg. The mean change in body weight from baseline to week 104 was −15.2% in the semaglutide group ( n = 152) versus −2.6% with placebo ( n = 152), for an estimated treatment difference of −12.6 %-points (95% confidence interval, −15.3 to −9.8; P &lt; 0.0001). More participants in the semaglutide group than in the placebo group achieved weight loss ≥5% from baseline at week 104 (77.1% versus 34.4%; P &lt; 0.0001). Gastrointestinal adverse events, mostly mild-to-moderate, were reported more often with semaglutide than with placebo (82.2% versus 53.9%). In summary, in adults with overweight (with at least one weight-related comorbidity) or obesity, semaglutide treatment led to substantial, sustained weight loss over 104 weeks versus placebo. NCT03693430
Clinical Efficacy and Whole-Exome Sequencing of Liquid Biopsies in a Phase IB/II Study of Bazedoxifene and Palbociclib in Advanced Hormone Receptor–Positive Breast Cancer
Authors: Junko Tsuji, Tianyu Li, Albert Grinshpun, Tim Coorens, Douglas Russo, Leilani Anderson, Rebecca Rees, Agostina Nardone, Candace Patterson, Niall J. Lennon, Carrie Cibulskis, Ignaty Leshchiner, Nabihah Tayob, Sara M. Tolaney, Nadine Tung, Donald P. McDonnell, Ian E. Krop, Eric P. Winer, Chip Stewart, Gad Getz, Rinath Jeselsohn
Journal: Clinical Cancer Research (2022)

Abstract Purpose: Sensitivity to endocrine therapy (ET) is critical for the clinical benefit from the combination of palbociclib plus ET in hormone receptor–positive/HER2-negative (HR+/HER2−) advanced breast cancer. Bazedoxifene is a third-generation selective estrogen receptor (ER) modulator and selective ER degrader with activity in preclinical models of endocrine-resistant breast cancer, including models harboring ESR1 mutations. Clinical trials in healthy women showed that bazedoxifene is well tolerated. Patients and Methods: We conducted a phase Ib/II study of bazedoxifene plus palbociclib in patients with HR+/HER2− advanced breast cancer who progressed on prior ET (N = 36; NCT02448771). Results: The study met its primary endpoint, with a clinical benefit rate of 33.3%, and the safety profile was consistent with what has previously been seen with palbociclib monotherapy. The median progression-free survival (PFS) was 3.6 months [95% confidence interval (CI), 2.0–7.2]. An activating PIK3CA mutation at baseline was associated with a shorter PFS (HR = 4.4; 95% CI, 1.5–13; P = 0.0026), but activating ESR1 mutations did not impact the PFS. Longitudinal plasma circulating tumor DNA whole-exome sequencing (WES; N = 68 plasma samples) provided an overview of the tumor heterogeneity and the subclonal genetic evolution, and identified actionable mutations acquired during treatment. Conclusions: The combination of palbociclib and bazedoxifene has clinical efficacy and an acceptable safety profile in a heavily pretreated patient population with advanced HR+/HER2− breast cancer. These results merit continued investigation of bazedoxifene in breast cancer.
The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK
Authors: Chen-Song Zhang, Mengqi Li, Yu Wang, Xiaoyang Li, Yue Zong, Shating Long, Mingliang Zhang, Jin-Wei Feng, Xiaoyan Wei, Yan-Hui Liu, Baoding Zhang, Jianfeng Wu, Cixiong Zhang, Wenhua Lian, Teng Ma, Xiao Tian, Qi Qu, Yaxin Yu, Jinye Xiong, Dong-Tai Liu, Zhenhua Wu, Mingxia Zhu, Changchuan Xie, Yaying Wu, Zheni Xu, Chunyan Yang, Junjie Chen, Guohong Huang, Qingxia He, Xi Huang, Lei Zhang, Xiufeng Sun, Qingfeng Liu, Abdul Ghafoor, Fu Gui, Kaili Zheng, Wen Wang, Zhi-Chao Wang, Yong Yu, Qingliang Zhao, Shu-Yong Lin, Zhi-Xin Wang, Hai-Long Piao, Xianming Deng, Sheng-Cai Lin
Journal: Nature Metabolism (2022)

The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.
Microbiome-derived ethanol in nonalcoholic fatty liver disease
Authors: Abraham S. Meijnikman, Mark Davids, Hilde Herrema, Omrum Aydin, Valentina Tremaroli, Melany Rios-Morales, Han Levels, Sjoerd Bruin, Maurits de Brauw, Joanne Verheij, Marleen Kemper, Adriaan G. Holleboom, Maarten E. Tushuizen, Thue W. Schwartz, Jens Nielsen, Dees Brandjes, Eveline Dirinck, Jonas Weyler, An Verrijken, Christophe E. M. De Block, Luisa Vonghia, Sven Francque, Ulrich Beuers, Victor E. A. Gerdes, Fredrik Bäckhed, Albert K. Groen, Max Nieuwdorp
Journal: Nature Medicine (2022)
Health effects associated with consumption of unprocessed red meat: a Burden of Proof study
Authors: Haley Lescinsky, Ashkan Afshin, Charlie Ashbaugh, Catherine Bisignano, Michael Brauer, Giannina Ferrara, Simon I. Hay, Jiawei He, Vincent Iannucci, Laurie B. Marczak, Susan A. McLaughlin, Erin C. Mullany, Marie C. Parent, Audrey L. Serfes, Reed J. D. Sorensen, Aleksandr Y. Aravkin, Peng Zheng, Christopher J. L. Murray
Journal: Nature Medicine (2022)

Abstract Characterizing the potential health effects of exposure to risk factors such as red meat consumption is essential to inform health policy and practice. Previous meta-analyses evaluating the effects of red meat intake have generated mixed findings and do not formally assess evidence strength. Here, we conducted a systematic review and implemented a meta-regression—relaxing conventional log-linearity assumptions and incorporating between-study heterogeneity—to evaluate the relationships between unprocessed red meat consumption and six potential health outcomes. We found weak evidence of association between unprocessed red meat consumption and colorectal cancer, breast cancer, type 2 diabetes and ischemic heart disease. Moreover, we found no evidence of an association between unprocessed red meat and ischemic stroke or hemorrhagic stroke. We also found that while risk for the six outcomes in our analysis combined was minimized at 0 g unprocessed red meat intake per day, the 95% uncertainty interval that incorporated between-study heterogeneity was very wide: from 0–200 g d −1 . While there is some evidence that eating unprocessed red meat is associated with increased risk of disease incidence and mortality, it is weak and insufficient to make stronger or more conclusive recommendations. More rigorous, well-powered research is needed to better understand and quantify the relationship between consumption of unprocessed red meat and chronic disease.
Growing pressure on NHS threatens frontline services
Authors: Adrian O'Dowd
Journal: BMJ (2022)

<h3>Objectives</h3> To establish the priorities of primary care providers to improve assessment and treatment of skin sores and sore throats among Aboriginal and Torres Strait Islander people at risk of acute rheumatic fever (ARF) and rheumatic heart disease (RHD). <h3>Design</h3> Modified eDelphi survey, informed by an expert focus group and literature review. <h3>Setting</h3> Primary care services in any one of the five Australian states or territories with a high burden of ARF. <h3>Participants</h3> People working in any primary care role within the last 5 years in jurisdiction with a high burden of ARF. <h3>Results</h3> Nine people participated in the scoping expert focus group which informed identification of an access framework for subsequent literature review. Fifteen broad concepts, comprising 29 strategies and 63 different actions, were identified on this review. These concepts were presented to participants in a two-round eDelphi survey. Twenty-six participants from five jurisdictions participated, 16/26 (62%) completed both survey rounds. Seven strategies were endorsed as high priorities. Most were demand-side strategies with a focus on engaging communities and individuals in accessible, comprehensive, culturally appropriate primary healthcare. Eight strategies were not endorsed as high priority, all of which were supply-side approaches. Qualitative responses highlighted the importance of a comprehensive primary healthcare approach as standard of care rather than disease-specific strategies related to management of skin sores and sore throat. <h3>Conclusion</h3> Primary care staff priorities should inform Australia’s commitments to reduce the burden of RHD. In particular, strategies to support comprehensive Aboriginal and Torres Strait Islander primary care services rather than an exclusive focus on discrete, disease-specific initiatives are needed.
Effects of elevated systolic blood pressure on ischemic heart disease: a Burden of Proof study
Authors: Christian Razo, Catherine A. Welgan, Catherine O. Johnson, Susan A. McLaughlin, Vincent Iannucci, Anthony Rodgers, Nelson Wang, Kate E. LeGrand, Reed J. D. Sorensen, Jiawei He, Peng Zheng, Aleksandr Y. Aravkin, Simon I. Hay, Christopher J. L. Murray, Gregory A. Roth
Journal: Nature Medicine (2022)

High systolic blood pressure (SBP) is a major risk factor for ischemic heart disease (IHD), the leading cause of death worldwide. Using data from published observational studies and controlled trials, we estimated the mean SBP-IHD dose-response function and burden of proof risk function (BPRF), and we calculated a risk outcome score (ROS) and corresponding star rating (one to five). We found a very strong, significant harmful effect of SBP on IHD, with a mean risk-relative to that at 100 mm Hg SBP-of 1.39 (95% uncertainty interval including between-study heterogeneity 1.34-1.44) at 120 mm Hg, 1.81 (1.70-1.93) at 130 mm Hg and 4.48 (3.81-5.26) at 165 mm Hg. The conservative BPRF measure indicated that SBP exposure between 107.5 and 165.0 mm Hg raised risk by 101.36% on average, yielding a ROS of 0.70 and star rating of five. Our analysis shows that IHD risk was already increasing at 120 mm Hg SBP, rising steadily up to 165 mm Hg and increasing less steeply above that point. Our study endorses the need to prioritize and strengthen strategies for screening, to raise awareness of the need for timely diagnosis and treatment of hypertension and to increase the resources allocated for understanding primordial prevention of elevated blood pressure.
Variants of the adeno-associated virus serotype 9 with enhanced penetration of the blood–brain barrier in rodents and primates
Authors: Yizheng Yao, Jun Wang, Yi Liu, Yuan Qu, Kaikai Wang, Yang Zhang, Yuxin Chang, Zhi Yang, Jie Wan, Junfeng Liu, Hiroshi Nakashima, Sean E. Lawler, E. Antonio Chiocca, Choi-Fong Cho, Fengfeng Bei
Journal: Nature Biomedical Engineering (2022)
Anti-tumor efficacy of a potent and selective non-covalent KRASG12D inhibitor
Authors: Jill Hallin, Vickie Bowcut, Andrew Calinisan, David M. Briere, Lauren Hargis, Lars D. Engstrom, Jade Laguer, James Medwid, Darin Vanderpool, Ella Lifset, David Trinh, Natalie Hoffman, Xiaolun Wang, J. David Lawson, Robin J. Gunn, Christopher R. Smith, Nicole C. Thomas, Matthew Martinson, Alex Bergstrom, Francis Sullivan, Karyn Bouhana, Shannon Winski, Leo He, Julio Fernandez-Banet, Adam Pavlicek, Jacob R. Haling, Lisa Rahbaek, Matthew A. Marx, Peter Olson, James G. Christensen
Journal: Nature Medicine (2022)
The Burden of Proof studies: assessing the evidence of risk
Authors: Peng Zheng, Ashkan Afshin, Stan Biryukov, Catherine Bisignano, Michael Brauer, Dana Bryazka, Katrin Burkart, Kelly M. Cercy, Leslie Cornaby, Xiaochen Dai, M. Ashworth Dirac, Kara Estep, Kairsten A. Fay, Rachel Feldman, Alize J. Ferrari, Emmanuela Gakidou, Gabriela Fernanda Gil, Max Griswold, Simon I. Hay, Jiawei He, Caleb M. S. Irvine, Nicholas J. Kassebaum, Kate E. LeGrand, Haley Lescinsky, Stephen S. Lim, Justin Lo, Erin C. Mullany, Kanyin Liane Ong, Puja C. Rao, Christian Razo, Marissa B. Reitsma, Gregory A. Roth, Damian F. Santomauro, Reed J. D. Sorensen, Vinay Srinivasan, Jeffrey D. Stanaway, Stein Emil Vollset, Theo Vos, Nelson Wang, Catherine A. Welgan, Sarah S. Wozniak, Aleksandr Y. Aravkin, Christopher J. L. Murray
Journal: Nature Medicine (2022)

Abstract Exposure to risks throughout life results in a wide variety of outcomes. Objectively judging the relative impact of these risks on personal and population health is fundamental to individual survival and societal prosperity. Existing mechanisms to quantify and rank the magnitude of these myriad effects and the uncertainty in their estimation are largely subjective, leaving room for interpretation that can fuel academic controversy and add to confusion when communicating risk. We present a new suite of meta-analyses—termed the Burden of Proof studies—designed specifically to help evaluate these methodological issues objectively and quantitatively. Through this data-driven approach that complements existing systems, including GRADE and Cochrane Reviews, we aim to aggregate evidence across multiple studies and enable a quantitative comparison of risk–outcome pairs. We introduce the burden of proof risk function (BPRF), which estimates the level of risk closest to the null hypothesis that is consistent with available data. Here we illustrate the BPRF methodology for the evaluation of four exemplar risk–outcome pairs: smoking and lung cancer, systolic blood pressure and ischemic heart disease, vegetable consumption and ischemic heart disease, and unprocessed red meat consumption and ischemic heart disease. The strength of evidence for each relationship is assessed by computing and summarizing the BPRF, and then translating the summary to a simple star rating. The Burden of Proof methodology provides a consistent way to understand, evaluate and summarize evidence of risk across different risk–outcome pairs, and informs risk analysis conducted as part of the Global Burden of Diseases, Injuries, and Risk Factors Study.
The Global Burden of Disease Study at 30 years
Authors: Christopher J. L. Murray
Journal: Nature Medicine (2022)

The Global Burden of Disease Study (GBD) began 30 years ago with the goal of providing timely, valid and relevant assessments of critical health outcomes. Over this period, the GBD has become progressively more granular. The latest iteration provides assessments of thousands of outcomes for diseases, injuries and risk factors in more than 200 countries and territories and at the subnational level in more than 20 countries. The GBD is now produced by an active collaboration of over 8,000 scientists and analysts from more than 150 countries. With each GBD iteration, the data, data processing and methods used for data synthesis have evolved, with the goal of enhancing transparency and comparability of measurements and communicating various sources of uncertainty. The GBD has many limitations, but it remains a dynamic, iterative and rigorous attempt to provide meaningful health measurement to a wide range of stakeholders. This Perspective reflects on the past, present and future of the dynamic, expanding public health endeavor that is the Global Burden of Disease Study.
Influence of the microbiome, diet and genetics on inter-individual variation in the human plasma metabolome
Authors: Lianmin Chen, Daria V. Zhernakova, Alexander Kurilshikov, Sergio Andreu-Sánchez, Daoming Wang, Hannah E. Augustijn, Arnau Vich Vila, Rinse K. Weersma, Marnix H. Medema, Mihai G. Netea, Folkert Kuipers, Cisca Wijmenga, Alexandra Zhernakova, Jingyuan Fu
Journal: Nature Medicine (2022)

The levels of the thousands of metabolites in the human plasma metabolome are strongly influenced by an individual's genetics and the composition of their diet and gut microbiome. Here, by assessing 1,183 plasma metabolites in 1,368 extensively phenotyped individuals from the Lifelines DEEP and Genome of the Netherlands cohorts, we quantified the proportion of inter-individual variation in the plasma metabolome explained by different factors, characterizing 610, 85 and 38 metabolites as dominantly associated with diet, the gut microbiome and genetics, respectively. Moreover, a diet quality score derived from metabolite levels was significantly associated with diet quality, as assessed by a detailed food frequency questionnaire. Through Mendelian randomization and mediation analyses, we revealed putative causal relationships between diet, the gut microbiome and metabolites. For example, Mendelian randomization analyses support a potential causal effect of Eubacterium rectale in decreasing plasma levels of hydrogen sulfite-a toxin that affects cardiovascular function. Lastly, based on analysis of the plasma metabolome of 311 individuals at two time points separated by 4 years, we observed a positive correlation between the stability of metabolite levels and the amount of variance in the levels of that metabolite that could be explained in our analysis. Altogether, characterization of factors that explain inter-individual variation in the plasma metabolome can help design approaches for modulating diet or the gut microbiome to shape a healthy metabolome.
Mendelian randomization analyses support causal relationships between brain imaging-derived phenotypes and risk of psychiatric disorders
Authors: Jing Guo, Ke Yu, Shan-Shan Dong, Shi Yao, Yu Rong, Hao Wu, Kun Zhang, Feng Jiang, Yi-Xiao Chen, Yan Guo, Tie-Lin Yang
Journal: Nature Neuroscience (2022)
Health effects associated with smoking: a Burden of Proof study
Authors: Xiaochen Dai, Gabriela F. Gil, Marissa B. Reitsma, Noah S. Ahmad, Jason A. Anderson, Catherine Bisignano, Sinclair Carr, Rachel Feldman, Simon I. Hay, Jiawei He, Vincent Iannucci, Hilary R. Lawlor, Matthew J. Malloy, Laurie B. Marczak, Susan A. McLaughlin, Larissa Morikawa, Erin C. Mullany, Sneha I. Nicholson, Erin M. O’Connell, Chukwuma Okereke, Reed J. D. Sorensen, Joanna Whisnant, Aleksandr Y. Aravkin, Peng Zheng, Christopher J. L. Murray, Emmanuela Gakidou
Journal: Nature Medicine (2022)

As a leading behavioral risk factor for numerous health outcomes, smoking is a major ongoing public health challenge. Although evidence on the health effects of smoking has been widely reported, few attempts have evaluated the dose-response relationship between smoking and a diverse range of health outcomes systematically and comprehensively. In the present study, we re-estimated the dose-response relationships between current smoking and 36 health outcomes by conducting systematic reviews up to 31 May 2022, employing a meta-analytic method that incorporates between-study heterogeneity into estimates of uncertainty. Among the 36 selected outcomes, 8 had strong-to-very-strong evidence of an association with smoking, 21 had weak-to-moderate evidence of association and 7 had no evidence of association. By overcoming many of the limitations of traditional meta-analyses, our approach provides comprehensive, up-to-date and easy-to-use estimates of the evidence on the health effects of smoking. These estimates provide important information for tobacco control advocates, policy makers, researchers, physicians, smokers and the public.
Health effects associated with vegetable consumption: a Burden of Proof study
Authors: Jeffrey D. Stanaway, Ashkan Afshin, Charlie Ashbaugh, Catherine Bisignano, Michael Brauer, Giannina Ferrara, Vanessa Garcia, Demewoz Haile, Simon I. Hay, Jiawei He, Vincent Iannucci, Haley Lescinsky, Erin C. Mullany, Marie C. Parent, Audrey L. Serfes, Reed J. D. Sorensen, Aleksandr Y. Aravkin, Peng Zheng, Christopher J. L. Murray
Journal: Nature Medicine (2022)

Previous research suggests a protective effect of vegetable consumption against chronic disease, but the quality of evidence underlying those findings remains uncertain. We applied a Bayesian meta-regression tool to estimate the mean risk function and quantify the quality of evidence for associations between vegetable consumption and ischemic heart disease (IHD), ischemic stroke, hemorrhagic stroke, type 2 diabetes and esophageal cancer. Increasing from no vegetable consumption to the theoretical minimum risk exposure level (306-372 g daily) was associated with a 23.2% decline (95% uncertainty interval, including between-study heterogeneity: 16.4-29.4) in ischemic stroke risk; a 22.9% (13.6-31.3) decline in IHD risk; a 15.9% (1.7-28.1) decline in hemorrhagic stroke risk; a 28.5% (-0.02-51.4) decline in esophageal cancer risk; and a 26.1% (-3.6-48.3) decline in type 2 diabetes risk. We found statistically significant protective effects of vegetable consumption for ischemic stroke (three stars), IHD (two stars), hemorrhagic stroke (two stars) and esophageal cancer (two stars). Including between-study heterogeneity, we did not detect a significant association with type 2 diabetes, corresponding to a one-star rating. Although current evidence supports increased efforts and policies to promote vegetable consumption, remaining uncertainties suggest the need for continued research.